tbuckley/cabot-search huggingface dataset:
ETMR-09.<i>In vitro</i> modelling of embryonal tumors with multilayered rosettes (ETMR) and other novel brain tumor types.
Authors: Jens Bunt, Mieke Roosen, Phylicia Stathi, Panagiotis Polychronopoulos, Zelda Odé, Joris Maas, Marcel Kool
Journal: Neuro-Oncology (2022)

Abstract Over the last decade, molecular characterization has resulted in many tumors previously classified as central nervous system primitive neuroectodermal tumors (CNS-PNETs) now being classified into their own distinct tumor types. These novel types are often characterized by very specific genomic aberrations. For instance, embryonal tumors with multilayered rosettes (ETMR) harbor amplifications of miRNA cluster C19MC or complex DICER1 mutations, while in CNS neuroblastoma with FOXR2 activation structural aberrations result in aberrant FOXR2 expression. Despite the presence of distinct oncodrivers, our understanding of these tumors is still limited. To elucidate tumor biology and to discover tumor specific treatments, we need to uncover how these oncodrivers contribute to tumorigenesis. However, a bottleneck in basic and translational research of these novel tumor types, is the lack of representative preclinical models, especially in vitro. To overcome this hurdle, we aim to mimic tumor development in genetically modified brain organoids. Human brain organoids derived from pluripotent stem cells are generated to represent either the developing forebrain or cerebellum. To mimic oncodriving events, DNA plasmids are introduced via electroporation into the proposed cell-of-origin populations to knockout tumor suppressor genes or overexpress oncogenes. By detecting fluorescent proteins encoded by the plasmids, electroporated cells are followed over time. Based on our preliminary data, for instance, overexpression of C19MC results in ectopic expansion of the electroporated cells. Ongoing histological and molecular characterizations, including (single cell) transcriptomic and epigenomic analyses, will reveal to which extend these organoid models resemble the specific human tumor types. Although further validation is required, these organoid models provide a novel avenue to study especially brain tumor types with distinct oncodriving events for which patient-derived models have not yet been established. They also allow for in-depth analyses of the potential cells of origin and the contribution of different mutations to tumor biology.
Phase Ib study of anlotinib in combination with anti-PD-L1 ab (TQB2450) in patients with advanced acral melanoma.
Authors: Lili Mao, Yu Chen, Yu Du, Xue Bai, Jie Dai, Jing Lin, Ling Chen, Zhihong Chi, Chuanliang Cui, Xinan Sheng, Bin Lian, Bixia Tang, Xuan Wang, Xiaoting Wei, Xieqiao Yan, Siming Li, Li Zhou, Juan Li, Jun Guo, Lu Si
Journal: Journal of Clinical Oncology (2022)

e21543 Background: Acral melanoma, the most common subtype of cutaneous malignant melanoma in Asians, is often diagnosed at an advanced stage but responds poorly to current PD-1/PD-L1 inhibitors. Here, we report an open-label, multicenter, single-arm, phase Ib study, aiming to evaluate the safety and efficacy of the combination therapy of TQB2450, a humanized monoclonal antibody against PD-L1 and anlotinib, an anti-angiogenic oral multi-target tyrosine kinase inhibitor in patients with advanced acral melanoma. Methods: Eligible patients were adults (ECOG PS of 0 or 1) with pathologically confirmed metastatic acral melanoma. In this dose-escalation and cohort-expansion study, patients received TQB2450 1200mg every 3 weeks in combination with anlotinib 10mg or 12mg once daily, 2-week on/1-week off until conformed disease progression, unacceptable toxicity, or voluntary withdrawal. The primary end points were dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and objective response rate (ORR). The secondary end points included adverse events, disease control rate (DCR), progression-free survival (PFS), overall survival (OS). Results: By December 8, 2021, 19 patients has been enrolled. The majority of patients (16 of 19 patients) were naive to systemic therapy. No DLT was observed. Eighteen (95%) of 19 patients experienced treatment-related adverse events (TRAEs), but most were grade 1 or 2. The most common TRAEs were hypothyroidism, hypertension, blood triglyceride elevation, hyperglycemia, blood cholesterol elevation, neutropenia, blood uric acid elevation, bilirubin elevation. Grade 3 or greater TRAEs occurred in 6 patients (31.6%). Among all patients with advanced acral melanoma assessed by investigator according to RECIST version 1.1, two patients achieved confirmed complete response and two patients achieved confirmed partial response. The ORR were 21.1% (95% CI, 6.1% to 45.6%). The DCR was 73.7% (95% CI, 48.8% to 90.9%). The median PFS time was 5.5 months (95% CI, 2.8 months to not reached) per RECIST version 1.1. The median OS was 20.3 months (95% CI, 10.2 months to not reached). Conclusions: The combination of TQB2450 plus anlotinib showed promising benefit and was tolerable in patients with advanced acral melanoma, which needed further investigation of the combination therapy in advanced acral melanoma. Clinical trial information: NCT03991975.
Incidental Detection of Radiotracer Uptake in Spindle Cell Lipoma on 18F-PSMA PET/CT
Authors: Nir Hod, Yehonatan Sherf, Sophie Lantsberg
Journal: Clinical Nuclear Medicine (2022)

Abstract An 84-year-old man underwent 18 F–prostate-specific membrane antigen (PSMA) PET/CT for staging of a newly diagnosed prostate adenocarcinoma. PET/CT revealed high 18 F-PSMA uptake in a thigh mass, which was initially suspected for a metastasis. Histopathology revealed a rare entity of spindle cell lipoma, which should be added to the reported list of neoplasms that can show “false-positive” PSMA uptake during evaluation of patients with prostate carcinoma representing a potential interpretative pitfall.
Racial disparities in diagnostic follow-up following BIRADS 0 mammogram.
Authors: Ritika Manik, Connor B. Grady, Sara Ginzberg, Christine E. Edmonds, Emily F. Conant, Rebecca A. Hubbard, Oluwadamilola Motunrayo Fayanju
Journal: Journal of Clinical Oncology (2022)

6559 Background: Delays in follow-up after abnormal mammograms can lead to worse outcomes and may contribute to health disparities. BIRADS 0 mammograms necessitate additional diagnostic imaging, and BIRADS 4 or 5 mammograms should be followed by biopsy. The goal of this study was to investigate racial disparities in rates and timeliness of (1) diagnostic follow-up after a BIRADS 0 screening mammogram and (2) biopsy following a subsequent BIRADS 4 or 5 diagnostic mammogram. Methods: We included women ≥18 years old who underwent a screening mammogram at the Hospital of the University of Pennsylvania with an assessment of BIRADS 0 between September 2010 and February 2018. The distributions of time from screening to diagnostic mammogram and from BIRADS 4 or 5 diagnostic mammogram to biopsy were estimated using the Kaplan Meier method. Follow-up was censored at 365 days. Case-mix adjusted Cox proportional hazards models were used to estimate the association between race/ethnicity and time to diagnostic mammogram and biopsy. Results: We identified 6299 women (Asian/PI=257, Black=3223, Hispanic=124, White=2420, Other/Unknown=275) with 6880 BIRADS 0 screening mammograms during the study period. Following these BIRADS 0 mammograms, the overall rate of diagnostic mammograms within 365 days was 87.3% (n=6006 mammograms), with a rate of 90.6% (2432) for White women and 85.3% (2971) for Black women. For the 1151 BIRADS 4-5 diagnostic mammograms in the cohort, the overall rate of follow-up biopsies within 365 days was 91.8% (n=1057 biopsies), with a rate of 93.8% (396) for White women and 91.1% (575) for Black women. Compared to mammograms obtained by White women, those obtained by Black women were less likely to be followed up with a diagnostic mammogram (HR 0.71, 95% CI 0.63-0.80, p&lt;0.001) and biopsy (HR 0.74, 95% CI 0.55-0.98, p=0.037) when indicated (Table). Almost 1/4 (24.2%, 95% CI 23.1-25.9%) of BIRADS 0 screening mammograms among Black women were not followed by diagnostic imaging within 30 days as compared to 14.6% among White women (95% CI 13.3-16.0%, p&lt;0.001). 23.6% (95% CI 20.5-27.2%) of BIRADS 4-5 diagnostic mammograms among Black women were not followed up with biopsy within 30 days vs 18.7% for White women (95% CI 15.4-22.8%, p=0.61) (Table). These disparities persisted at 90 days. Conclusions: Racial disparities exist in rates of follow-up after BIRADS 0 mammograms. The additive effects of delays at each diagnostic step put Black women at disproportionately greater risk for worse outcomes. [Table: see text]
Short-term effectiveness of high-load compared with low-load strengthening exercise on self-reported function in patients with hypermobile shoulders: a randomised controlled trial
Authors: Behnam Liaghat, Søren T Skou, Jens Søndergaard, Eleanor Boyle, Karen Søgaard, Birgit Juul-Kristensen
Journal: British Journal of Sports Medicine (2022)

To investigate the short-term effectiveness of high-load versus low-load strengthening exercise on self-reported function in patients with hypermobility spectrum disorder (HSD) and shoulder symptoms.
A phase IB/II study of nivolumab in combination with eribulin in HER2-negative metastatic breast cancer (KCSG BR18-16).
Authors: Se Hyun Kim, Koung Jin Suh, Seock-Ah Im, Kyung-Hun Lee, Min Hwan Kim, Joohyuk Sohn, Yeon Hee Park, Ji-Yeon Kim, Jae Ho Jeong, Kyoung Eun Lee, In Sil Choi, Kyong Hwa Park, Hee Jun Kim, Eun Kyung Cho, So Yeon Park, Milim Kim, Jee Hyun Kim
Journal: Journal of Clinical Oncology (2022)

1098 Background: Combining immune checkpoint inhibitors with chemotherapy has become a promising therapeutic strategy in metastatic breast cancer. Eribulin is a potent microtubule inhibitor and modulates the immune microenvironment of tumor cells. Therefore, combining eribulin to nivolumab may synergize antitumor efficacy in metastatic breast cancer. Methods: Adult patients with histologically confirmed recurrent/metastatic HER2- breast cancer were enrolled prospectively from 10 academic hospitals in Korea (ClinicalTrials.gov Identifier: NCT04061863). Key eligibility criteria included prior treatment with taxanes and/or anthracyclines, ≥1 measurable disease, and ≤2 prior cytotoxic chemotherapies in the metastatic setting. Patients received nivolumab 200 mg intravenously (IV) on day 1 plus eribulin 1.4 mg/m 2 IV on day 1 and 8 of every 3 weeks until disease progression or intolerable toxicity. The dose level was determined from safety profile of three patients in run-in phase. The primary endpoint was investigator-assessed progression-free survival (PFS) rate at 6 months. Secondary endpoints included investigator-assessed objective response rate (ORR) per RECIST v1.1, disease control rate (DCR), overall survival (OS), and toxicity profile of the combination treatment. The association between PD-L1 expression by SP142 Ab and efficacy was analyzed. Results: From August 2019 to June 2021, 90 patients (HR+HER2- 45 pts/TNBC 45 pts), with a median age of 51 (range 31–71), were enrolled in the study. With a median study follow-up time of 16.3 months, 68 (75.6%) patients experienced progressive disease. PFS rate at 6-months was 49.6% and 24.1% in patients with HR+HER2- and TNBC group, respectively. Median PFS was 5.6 months (95% CI: 4.3-6.8) and 3.0 months (95% CI: 1.3-4.7) for HR+HER2- and TNBC group, respectively. ORRs were 53.3% (CR:0, PR: 24) for HR+HER2- and 21.8% (CR1, PR: 12) for TNBC. Patients with PD-L1+ tumors (PD-L1 expression ≥ 1% on TC or IC) had similar ORR compared to PD-L1- tumors (ORR 50% vs. 53.8% in HR+HER2-, 30.8% vs. 29.0% in TNBC). The most common grade 3/4 adverse event was neutropenia (15/90, 16.7%), and the most common immune-related adverse events were grade 1/2 hypothyroidism (19/90, 21.1%) and grade 1/2 pruritus (16/90, 17.8%). Five patients had discontinued study treatment due to immune-related adverse events (3 pneumonitis, 1 hepatitis, 1 skin rash). Conclusions: In this parallel phase II clinical trial, the addition of nivolumab to eribulin showed promising efficacy and tolerable safety profile in previously treated HER2- MBC. Further survival and exploratory analyses to find predictive markers will be followed. Clinical trial information: NCT04061863. [Table: see text]
MODL-30. Children’s Brain Tumor Network preclinical tumor models development and sharing platform: collaborative model empowering pediatric brain tumor discovery and global research.
Authors: Mateusz Koptyra, Valerie Baubet, David Beale, Luke Patterson, Ian Biluck, Madison Hollawell, Christopher M Beck, Poonam Sonawane, Crystal Griffin, Allison Stern, Peter Madsen, Jessica Foster, Jena Lilly, Jennifer Mason, Gerri Trooskin, Catherine Sullivan, Allison Morgan, Beth Frenkel, Kaitlin Lehmann, Lina Lopez, Thinh Nguyen, Ena Agbodza, Valeria Lopez-Gil, Zeinab Helili, Alexa Plisiewicz, Noel Coleman, Tatiana Patton, Stephanie Stefankiewicz, Kamnaa Arya, Ryan Velasco, Mariarita Santi, Angela Viaene, Phillip B Storm, Adam Resnick
Journal: Neuro-Oncology (2022)

Abstract Pediatric brain tumor preclinical field suffered for years from the lack of in vitro and in vivo models. With the explosion of novel therapy approaches for solid and brain tumors, including the immunotherapies it is essential to maximize the access to preclinical models for preclinical specificity, efficacy as well and safety. One of the many ways the Children’s Brain Tumor Network (CBTN) accelerates the pediatric brain tumor research and discovery is through support of the tumor model development program. This program focuses on the generation, characterization, and distribution of diverse models to investigators worldwide provided free of charge. Here we present the resource platform with over 150 cell lines, organoids and patient derived xenografts (PDX) developed and/or propagated at D3b at CHOP on behalf of CBTN. This platform maximizes the tumor tissue use to generate a combination of cell line, organoids and/or xenograft models grown in animals. In recent years, consortium supported over 40 requests for cells lines used in basic biology and translational studies internationally. Current efforts focusing also on supporting large-scale data generation and testing through its collaborative model (Childhood Cancer Model Atlas, Procan, National Center for Advancing Translational Sciences) to maximize the molecular information available for each tumor model essential in preclinical screenings. The generated and returned to consortia data are bound with the deidentified patient clinical information and genomic data and freely available through Kid’s First Data, Cavatica and PedcBio portals. These efforts have already attracted interest from pharma stakeholders previously not observed in pediatric brain environment. This open-source repository model is an example of a unique research partnership supported by patients and their families and built with one mission to bring fast change to kids suffering from brain tumors.
HGG-43. Abrogation of exosome biogenesis significantly affects cell motility in heterogenous sub-populations of paediatric-type diffuse high-grade glioma
Authors: Giulia Pericoli, Angela Galardi, Lucia Lisa Petrilli, Alessandro Paolini, Stefano Levi Mortera, Gerardo Pepe, Alessandro Palma, Emmanuel de Billy, Roberta Ferretti, Marta Colletti, Ezio Giorda, Anna Burford, Alan Mackay, Luisa Pascucci, Hector Peinado, Chris Jones, Manuela Helmer Citterich, Lorenza Putignani, Andrea Carai, Angela Mastronuzzi, Andrea Masotti, Franco Locatelli, Angela Di Giannatale, Maria Vinci
Journal: Neuro-Oncology (2022)

Abstract Paediatric-type diffuse High-Grade Gliomas (PDHGG) are highly heterogenous tumours comprised of distinct cell sub-populations co-existing within the same tumour mass. We have shown that primary patient-derived sub-clones, as well as optical-barcoded sub-clones, function as an interconnected network conferring an aggressive phenotype. Here, we explored the role of exosomes in mediating PDHGG inter-clonal communication. A comprehensive characterization of 7 optical-barcoded single cell-derived clones obtained from two patient-derived cell lines (one DMGH3K27-altered and one diffuse high-grade paediatric-type glioma H3WT), confirmed extensive genomic and phenotypic heterogeneity. Live single-cell tracking in 3D migration and invasion assays demonstrated the key role of the inter-clonal crosstalk in driving a more aggressive phenotype. To determine the exosome role in this crosstalk, we first characterised them in terms of size, marker expression and cargo. Moreover, we demonstrated that exosomes were actively internalized by the sub-clones. Exosomal proteomic analysis showed differential protein contents implicated in the regulation of biological processes such as focal adhesion and extracellular matrix organization. The analysis of exosomal miRNome did not show differentially expressed miRNAs between sub-clones, however, specific and distinct exosomal miRNAs were found uniquely expressed by each sub-clone. The abrogation of the exosome biogenesis by GW4869 phospholipase inhibitor did not affect sub-clones viability, but significantly inhibited their motility, when cultured individually and more prominently in co-culture condition. Analysis of the exo-miRNAs uniquely expressed by the sub-clones highlighted a set of target genes regulating cell motility/invasion/migration. These target genes were differentially expressed when sub-clones were co-cultured compared to mono-culture. Moreover, the expression levels of these genes (e.g. CD44, PTRZ, GLI3, NTRK2) were significantly modulated upon GW4869 treatments. In conclusion, our study highlights the importance of the exosomes in the inter-clonal communication and suggests that interfering with the exosome biogenesis may be a valuable strategy to inhibit cell motility in PDHGG.
Long-term predictive value of serum PSA values obtained in clinical practice: Results from the Norwegian Prostate Cancer Consortium (NPCC).
Authors: Jan Oldenburg, Johan Lars Bjerner, Hans Lilja, Kirsti Aas, Sophie D. Fossa, Christoph Mueller, Stig Mueller, Owen Thomas, Andreas Stensvold, Jochen Walz, Oluf D. Røe, Ola Bratt, Sigrid V. Carlsson
Journal: Journal of Clinical Oncology (2022)

5021 Background: A baseline prostate-specific antigen (PSA) level in midlife is strongly associated with risk of lethal prostate cancer several decades later. In most prior studies, PSA was measured in archived blood from men participating in cohort studies unrelated to prostate cancer. In clinical practice, however, men commonly obtain a PSA test because of lower urinary tract symptoms. Here, we study the association between PSA values when a first PSA test was obtained as part of clinical care – and subsequent risks of prostate cancer diagnosis and death. Methods: The NPCC database contained laboratory results from 1995-2006 of the first (“baseline”) PSA test below 4.0 ng/mL in 157,836 men aged 40-69 years without prior prostate cancer (PCa) diagnosis. PSA strata were pre-defined: &lt; 1, 1-1.99, 2-2.99, 3-3.99 ng/ml and analyses were split in two age groups based on a prior risk: 40-54 (“younger”) and 55-69 (“older”). Predictive accuracy was assessed with Harrell’s concordance (C) index. The Kaplan-Meier method was used to visualize risk of PCa death as reported on the death certificate by PSA strata for the two age groups. Results: Among 157,836 men with a PSA below 4.0 ng/mL, 83% had &lt; 2.0 ng/mL. Risk of prostate cancer and death from prostate cancer were strongly associated with PSA-levels and age: Harrell’s C-index 0.75 and 0.72 for diagnosis of younger and older group, respectively and 0.72 for PCa death for both age groups. In the younger age group 196 deaths among 75,446 men (0.26%) were registered, in the older 943 deaths among 82,390 men (1.14%). The risk of PCa death in lowest (&lt; 1) and highest (3-3.99) strata were 0.23% and 3.22%, respectively (189 deaths among 81,982 vs. 274 deaths among 8517 men). Conclusions: This population-based NPCC study shows as strong predictive impact of the different strata of the initial PSA measurement in routine clinical care as prior studies based on cryopreserved blood samples. [Table: see text]
Efficacy and safety of transcatheter arterial chemoembolization in combination with camrelizumab and targeted agents in intermediate-stage unresectable hepatocellular carcinoma: A single-arm, prospective, real-world study.
Authors: Jinpeng Li, Jutian Shi, Jinlong Song
Journal: Journal of Clinical Oncology (2022)

e16190 Background: The prognosis for advanced hepatocellular carcinoma (HCC) is still very poor. This study aimed to explore the efficacy and safety of transcatheter arterial chemoembolization (TACE) combined with camrelizumab plus targeted therapy for the treatment of patients with advanced HCC. Methods: In this single-arm, prospective, real-world study, patients with intermediate-stage unresectable HCC who had a Child-Pugh score ≤ 7 and had not received prior systemic anti-cancer treatment would receive comprehensive treatment with TACE followed by immunotherapy with camrelizumab 200 mg every 3 weeks plus a tyrosine kinase inhibitor (TKI) agent selected from lenvatinib (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight &lt; 60 kg), sorafenib 400 mg twice-daily or donafenib 200 mg twice-daily until intolerable toxicity or disease progression. During the study treatment, patients assessed as eligible for resection would undergo surgery. The primary endpoint was objective response rate (ORR) assessed by an independent review committee per modified RECIST. Secondary endpoints included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Results: From September 2020 to November 2021, 49 patients were enrolled. Among them, 45 (91.8%) patients were male, 41 (83.7%) patients were aged ≤65 years, 30 (61.2%) patients had extrahepatic metastases, and 41 (83.7%) patients had HBV infection. The ORR and DCR were 69.4% (34/49) and 87.8% (43/49), respectively. Five (10.2%) patients were assessed as eligible for surgery, and one of them already received surgery successfully and achieved pathological complete response. The median OS was not reached, and the median PFS was 6.1 months (95%CI, 1.4 -10.8). After 3 months, the alpha-feto-protein decreased compared with before treatment (p &lt; 0.05). All patients had adverse events (AEs) of any grade. The most common AEs were reactive cutaneous capillary endothelial proliferation (30, 61.2%), abdominal pain (25, 51.0%), thyroid dysfunction (20, 40.8%) and fever (18, 36.7%). The majority of treatment-related AEs (TRAEs) were mild or moderate. Grade 3 TRAEs occurred in 3 (6.1%) patients, grade 4 TRAEs occurred in 1 (2.0%) patient, and no deaths occurred. Conclusions: TACE combined with camrelizumab plus targeted therapy in the treatment of advanced HCC shows good efficacy in controlling tumor progression and may provide opportunity of resection. Clinical trial information: ChiCTR2000039508.